Melanoma is a highly aggressive cancer with an alarmingly increasing incidence. A major question in melanoma biology is why are red-haired individuals at a high risk of developing melanoma. Variants in the melanocortin-1-receptor (MC1R) gene, encoding a trimeric G protein- coupled receptor activated by a-melanocyte-stimulating hormone (a-MSH), are frequently associated with red or blonde hair, fair skin, freckling and skin sensitivity to ultraviolet (UV) light, and several (RHC-variants) also associate with increased melanoma risk. Several of these variants are associated with increased melanoma risk. However, not all of these associations have been attributed to phenotype, suggesting that some variants affect melanoma risk independent of phenotype. Using an in vivo model system, we recently reported that some MC1R mutations synergize with UV to induce melanoma independently of their effects on pigmentation. Understanding precisely how MC1R RHC-variants differentially affect melanoma biology is therefore a key issue. Importantly, we also reported recently that UV irradiation triggered MC1R-interaction with and degradation of PTEN, leading to increased PI3K- signalling-driven senescence in melanocytes, but senescence bypass in BRaf mutant melanoma. Importantly, WT MC1R but not red-hair associated MC1R RHC-variants could interact with PTEN. Here, we will use newly generated MC1R conditional RHC-variant mouse models to dissect the tumor suppressive functions of MC1R in melanoma initiation in vivo and specifically its role in controlling PI3K signaling via PTEN degradation. We will also undertake the in-depth mechanistic studies required to identify potential targets for therapeutic intervention. Finally, we will develop novel preventive and therapeutic strategies in melanoma guided by the in-depth molecular mechanism(s) in the MC1R/PTEN interaction. Our proposed studies will identify intracellular molecular targets of MC1R in suppressing melanoma initiation that are directed towards identifying novel strategies for melanoma prevention and therapeutic intervention.